Early growth response-1 is a regulator of DR5-induced apoptosis in colon cancer cells

D. Mahalingam, A. Natoni, M. Keane, A. Samali, E. Szegezdi

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour cell apoptosis by binding to death receptor 4 (DR4) and DR5. DR4 and DR5 activation however can also induce inflammatory and pro-survival signalling. It is not known how these different cellular responses are regulated and what the individual role of DR4 vs DR5 is in these processes. Methods:DNA microarray study was carried out to identify genes differentially expressed after DR4 and DR5 activation. RT-PCR and western blotting was used to examine the expression of early growth response gene-1 (Egr-1) and the proteins of the TRAIL signalling pathway. The function of Egr-1 was studied by siRNA-mediated knockdown and overexpression of a dominant-negative version of Egr-1.results: We show that the immediate early gene, Egr-1, regulates TRAIL sensitivity. Egr-1 is constitutively expressed in colon cancer cells and further induced upon activation of DR4 or DR5. Our results also show that DR4 mediates a type II, mitochondrion-dependent apoptotic pathway, whereas DR5 induces a mitochondrion-independent, type I apoptosis in HCT15 colon carcinoma cells. Egr-1 drives c-FLIP expression and the short splice variant of c-FLIP (c-FLIPS) specifically inhibits DR5 activation.Conclusion:Selective knockdown of c-FLIP S sensitises cells to DR5-induced but not DR4-induced apoptosis and Egr-1 exerts an effect as an inhibitor of the DR5-induced apoptotic pathway, possibly by regulating the expression of c-FLIP S.

Original languageEnglish (US)
Pages (from-to)754-764
Number of pages11
JournalBritish Journal of Cancer
Volume102
Issue number4
DOIs
StatePublished - Feb 2010

Fingerprint

TNF-Related Apoptosis-Inducing Ligand Receptors
Colonic Neoplasms
Apoptosis
Growth
Genes
CASP8 and FADD-Like Apoptosis Regulating Protein
Mitochondria
Immediate-Early Genes
Oligonucleotide Array Sequence Analysis
Small Interfering RNA
Colon
Tumor Necrosis Factor-alpha
Western Blotting
Ligands
Carcinoma
Polymerase Chain Reaction

Keywords

  • Cellular FLICE inhibitory protein (c-FLIP)
  • Colon carcinoma
  • Death receptor 5 (DR5)
  • Early growth response gene-1 (Egr-1)
  • Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)
  • Type I extrinsic apoptotic pathway

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Early growth response-1 is a regulator of DR5-induced apoptosis in colon cancer cells. / Mahalingam, D.; Natoni, A.; Keane, M.; Samali, A.; Szegezdi, E.

In: British Journal of Cancer, Vol. 102, No. 4, 02.2010, p. 754-764.

Research output: Contribution to journalArticle

Mahalingam, D, Natoni, A, Keane, M, Samali, A & Szegezdi, E 2010, 'Early growth response-1 is a regulator of DR5-induced apoptosis in colon cancer cells', British Journal of Cancer, vol. 102, no. 4, pp. 754-764. https://doi.org/10.1038/sj.bjc.6605545
Mahalingam, D. ; Natoni, A. ; Keane, M. ; Samali, A. ; Szegezdi, E. / Early growth response-1 is a regulator of DR5-induced apoptosis in colon cancer cells. In: British Journal of Cancer. 2010 ; Vol. 102, No. 4. pp. 754-764.
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AB - Background: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour cell apoptosis by binding to death receptor 4 (DR4) and DR5. DR4 and DR5 activation however can also induce inflammatory and pro-survival signalling. It is not known how these different cellular responses are regulated and what the individual role of DR4 vs DR5 is in these processes. Methods:DNA microarray study was carried out to identify genes differentially expressed after DR4 and DR5 activation. RT-PCR and western blotting was used to examine the expression of early growth response gene-1 (Egr-1) and the proteins of the TRAIL signalling pathway. The function of Egr-1 was studied by siRNA-mediated knockdown and overexpression of a dominant-negative version of Egr-1.results: We show that the immediate early gene, Egr-1, regulates TRAIL sensitivity. Egr-1 is constitutively expressed in colon cancer cells and further induced upon activation of DR4 or DR5. Our results also show that DR4 mediates a type II, mitochondrion-dependent apoptotic pathway, whereas DR5 induces a mitochondrion-independent, type I apoptosis in HCT15 colon carcinoma cells. Egr-1 drives c-FLIP expression and the short splice variant of c-FLIP (c-FLIPS) specifically inhibits DR5 activation.Conclusion:Selective knockdown of c-FLIP S sensitises cells to DR5-induced but not DR4-induced apoptosis and Egr-1 exerts an effect as an inhibitor of the DR5-induced apoptotic pathway, possibly by regulating the expression of c-FLIP S.

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